This research proposal describes a 5-year plan for the development of an academic career in patient-oriented clinical pain research. The goal of this career development proposal is to expand the applicant' s scientific skills through mentored training in pain, clinical pharmacology, and epidemiologic research in order to become a successful independently-funded clinical scientist. The Candidate: Larry F. Chu, MD, MS is an Assistant Professor (appointment pending) in the Department of Anesthesia at the Stanford University School of Medicine. His short-term career goal is to obtain additional training in the principles and practice of clinical pain research through close research mentorship and formal training in clinical epidemiology. His long-term career goal is to develop a patient-oriented research program that focuses on characterizing neuroplastic changes associated with the pharmacologic treatment of chronic pain. Research Environment: Dr. Chu will be mentored by Dr. David Clark, Assistant Professor and Chief of the Palo Alto VA Pain Service, who will provide expertise in clinical pain management and pain research techniques. To enhance the training, Dr. Steven Shafer will provide expertise in the principles of clinical pharmacology. Dr. Shafer is an internationally-recognized investigator in clinical pharmacology who has a long and productive history of training postdoctoral fellows and mentoring junior clinical scientists. Formal didactic training in the principles of clinical research will be provided through completion of Stanford's K30 Clinical Research Training Program. Dr. Chu has been accepted into the 45-unit program, which will be completed over two years and result in a Master's Degree in Clinical Epidemiology. In addition, an interdisciplinary advisory committee of accomplished scientists and clinical researchers will provide additional scientific and career guidance. Research Plan: The applicant's research will focus on characterizing neuroplastic changes associated with chronic opioid therapy in patients with chronic pain. Opiates such as morphine are the cornerstone medications for the treatment of moderate to severe pain. Recent evidence suggests that pain patients on chronic opioid therapy become more sensitive to pain (hyperalgesia) over time. There is also a long-standing notion that analgesic tolerance to opioids (habituation) develops during chronic use even though this phenomenon has never been prospectively studied. Our specific aims propose to prospectively test the hypotheses that; 1) Pain patients on chronic opioid therapy develop dose-dependent tolerance and/or hyperalgesia to these medications over time, 2) Opioid-induced tolerance and hyperalgesia develop differently with respect to various types of pain, 3) Opioid-induced hyperalgesia occurs independently of withdrawal phenomena, and 4) Opioid-induced tolerance and hyperalgesia develop differently based on gender and/or ethnicity. This proposed study will be the first quantitative and prospective study of tolerance and hyperalgesia in pain patients and will have important implications for the rational use of opioids in the treatment of chronic pain.